The present invention relates to new ester derivatives of alkoxybenzoyldeoxyfluorouridine of the general formula: ##STR2## wherein R stands for an alkoxy group having 1 to 4 carbon atoms, m for 1 or 2, and n for 3 or 4 and when m is 2, the adjacent two R's may be combined to form an alkylenedioxy group as a whole. The present invention further relates to a process for the preparation of the ester derivatives and anti-tumor agents containing the ester derivatives as an active ingredient.
2'-Deoxy-5-fluorouridine (referred to hereinafter as FUDR) has been used as an anti-tumor agent but this compound is exceptionally high in toxicity for use as a medication and thus has a narrow safety region. In addition, this compound has considerable limitations in actual therapeutic applications since the mode of administering this compound is limited only to intraarterial injection, or in other words, this compound cannot be administered orally [Physicians' Desk Reference, p. 1387 (1978)]. 2'-Deoxy-3',5'-di-O-acetyl-5-fluorouridine (referred to hereinafter simply as acetyl-FUDR) is also known as one of the FUDR derivatives. However, this compound is evaluated as being almost equivalent in anti-tumor activity to FUDR and rather poor in effectiveness [Biochem. Pharmacology, 14, 1605 et seq., (1965); Cancer Research, 23, 420 et seq. (1963)].
3',5'-Dialkyl esters of FUDR are also reported as derivatives of FUDR [Biochem. Pharmacology, 14, 1605-1619 (1965), ibid. 15, 627-644 (1966)]. However, no compound was found which was satisfactory with respect to anti-tumor activity and toxicity. Recently, reported FUDR and acetyl-FUDR derivatives are such compounds wherein the hydrogen atom bonded to the nitrogen atom at the 3-position on the uracil ring is substituted by a specific aroyl group (U.K. Patent Appln. Ser. No. 2,025,401 published on Jan. 23, 1980 and European Patent Appln. Ser. No. 9,882 published on Apr. 16, 1980). However, further enhancement in anti-tumor activity is desired also in these compounds. Thus, there is a great demand for developing new FUDR derivatives which possess strong anti-tumor activity with weak toxicity and are suited for oral administration without the necessity of using troublesome intraarterial for intravenous injection.
As a result of extensive research made on a variety of FUDR derivatives for enhancing their anti-tumor activity and concurrently reducing their toxicity, it has now been surprisingly found that the new compounds of the general formula (1) are superior in anti-tumor activity to the known similar compounds at an equivalent toxicity level. The present invention has been accomplished on the basis of the above finding.
In the general formula (I), the alkoxy group having 1 to 4 carbon atoms represented by R may be a straight or branched chain alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy and the like.
When two vicinal lower alkoxy groups exist as ring-substituents in the benzoyl group (R=a lower alkoxy group and m=2), the alkyl moieties of the two lower alkoxy groups may be combined to form an alkylene group. In this case, the two vicinal lower alkoxy group form an alkylenedioxy group as a whole. Preferable examples of the alkylenedioxy group include methylenedioxy, ethylenedioxy and propylenedioxy groups.
The new compounds of the general formula (I) of the present invention are prepared, for example, by reacting a 2'-dioxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine of the general formula: ##STR3## wherein n has the same meaning as given above, with a benzoyl halide of the general formula: ##STR4## wherein R and m have the same meaning as given above and hal is a halogen atom.
The benzoyl chloride or bromide as a benzoyl halide of the starting material, is preferably used.
The benzoyl halide of the general formula (III) is preferably used in an amount of 1-3 molar proportion for the 2'-deoxy-3',5'-di-O-alkylcarbonyl-5-fluorouridine.
The reaction is preferably carried out as a rule in an organic solvent. Illustrative of the preferable organic solvents are aprotic solvents such as ether, dioxane, chloroform, ethyl acetate, acetonitrile, pyridine, dimethylformamide and the like.
The reaction is carried out normally in the presence of an organic base, especially aromatic amines such as pyridine, trialkylamines or N,N-dialkylanilines.
The organic base is used usually in an amount of 1-5 moles per mole of the benzoyl halide. As the organic bases per se may be used as the reaction medium, an excess amount of the organic base may be used in place of a part or all of the reaction solvent.
The reaction is carried out within a wide range of reaction temperatures, for example, under ice cooling or at a temperature up to the boiling point of the raction solvent used. As a rule, the reaction time is preferably within a period of from 30 minutes to 12 hours.
After completion of the reaction, the end product can be obtained by subjecting the reaction mixture directly to concentration under reduced pressure or by first filtering the reaction mixture and then concentrating the filtrate under reduced pressure, and finally recrystallizing the resultant residue or subjecting the residue to chromatography. When the end product is isolated as a viscous oily substance, it can be obtained as a solid form by dissolving the oily substance in a small amount of dimethylsulfoxide and slowly pouring the solution into water with agitation.
The products of the present invention possess high anti-tumor activity with weak toxicity as compared with the known similar FUDR derivatives. The pharmacological tests for the thus obtained compounds of the present invention were carried out as follows.